1. Field of the Invention
This invention relates to a respirable dry powder formulation comprising a pharmaceutically or veterinarily acceptable carrier and a dehydroepiandrosterone (DHEA), DHEA derivative, or pharmaceutically or veterinarily acceptable salt thereof, sealed in a nebulizable form. Methods for preparation and delivering of the dry powdered formulation, and for treating asthma, chronic obstructive pulmonary disease (COPD), or other respiratory disease or condition, including microbial (including bacteria) or viral caused respiratory disease, such as severe acute respiratory syndrome (SARS). The formulation is provided in the form of a kit.
2. Description of the Background
Asthma and COPD and other respiratory ailments, associated with a variety of diseases and conditions, are extremely common in the general population, and more so in certain ethnic groups, such as African Americans. Respiratory ailments include microbial infections or viral infections (such as SARS). In many cases they are accompanied by inflammation, which aggravates the condition of the lungs. Asthma, for example, is one of the most common diseases in industrialized countries. In the United States it accounts for about 1% of all health care costs. An alarming increase in both the prevalence and mortality of asthma over the past decade has been reported, and asthma is predicted to be the preeminent occupational lung disease in the next decade. While the increasing mortality of asthma in industrialized countries could be attributable to the reliance upon beta agonists in the treatment of this disease, the underlying causes of asthma remain poorly understood.
Asthma is a condition characterized by variable, in many instances reversible obstruction of the airways. This process is associated with lung inflammation and in some cases lung allergies. Many patients have acute episodes referred to as “asthma attacks,” while others are afflicted with a chronic condition. The asthmatic process is believed to be triggered in some cases by inhalation of antigens by hypersensitive subjects. This condition is generally referred to as “extrinsic asthma.” Other asthmatics have an intrinsic predisposition to the condition, which is thus referred to as “intrinsic asthma,” and may be comprised of conditions of different origin, including those mediated by the adenosine receptor(s), allergic conditions mediated by an immune IgE-mediated response, and others. All asthmas have a group of symptoms, which are characteristic of this condition: bronchoconstriction, lung inflammation and decreased lung surfactant. Existing bronchodilators and anti-inflammatories are currently commercially available and are prescribed for the treatment of asthma. The most common anti-inflammatories, corticosteroids, have considerable side effects but are commonly prescribed nevertheless. Most of the drugs available for the treatment of asthma are, more importantly, barely effective in a small number of patients.
Chronic obstructive pulmonary disease (COPD) causes a continuing obstruction of airflow in the airways. COPD is characterized by airflow obstruction that is generally caused by chronic bronchitis, emphysema, or both. Commonly, the airway obstruction is mostly irreversible. In chronic bronchitis, airway obstruction results from chronic and excessive secretion of abnormal airway mucus, inflammation, bronchospasm, and infection. Chronic bronchitis is also characterized by chronic cough, mucus production, or both, for at least three months in at least two successive years where other causes of chronic cough have been excluded. In emphysema, a structural element (elastin) in the terminal bronchioles is destroyed leading to the collapse of the airway walls and inability to exhale “stale” air. In emphysema there is permanent destruction of the alveoli. Emphysema is characterized by abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. COPD can also give rise to secondary pulmonary hypertension. Secondary pulmonary hypertension itself is a disorder in which blood pressure in the pulmonary arteries is abnormally high. In severe cases, the right side of the heart must work harder than usual to pump blood against the high pressure. If this continues for a long period, the right heart enlarges and functions poorly, and fluid collects in the ankles (edema) and belly. Eventually the left heart begins to fail. Heart failure caused by pulmonary disease is called cor pulmonale.
COPD characteristically affects middle aged and elderly people, and is one of the leading causes of morbidity and mortality worldwide. In the United States it affects about 14 million people and is the fourth leading cause of death, and the third leading cause for disability in the United States. Both morbidity and mortality, however, are rising. The estimated prevalence of this disease in the United States has risen by 41% since 1982, and age adjusted death rates rose by 71% between 1966 and 1985. This contrasts with the decline over the same period in age-adjusted mortality from all causes (which fell by 22%), and from cardiovascular diseases (which fell by 45%). In 1998 COPD accounted for 112,584 deaths in the United States.
COPD, however, is preventable, since it is believed that its main cause is exposure to cigarette smoke. Long-term smoking is the most frequent cause of COPD. It accounts for 80 to 90% of all cases. A smoker is 10 times more likely than a non-smoker to die of COPD. The disease is rare in lifetime non-smokers, in whom exposure to environmental tobacco smoke will explain at least some of the airways obstruction. Other proposed etiological factors include airway hyper responsiveness or hypersensitivity, ambient air pollution, and allergy. The airflow obstruction in COPD is usually progressive in people who continue to smoke. This results in early disability and shortened survival time. Stopping smoking reverts the decline in lung function to values for non-smokers. Other risk factors include: heredity, second-hand smoke, exposure to air pollution at work and in the environment, and a history of childhood respiratory infections. The symptoms of COPD include: chronic coughing, chest tightness, shortness of breath, an increased effort to breathe, increased mucus production, and frequent clearing of the throat.
There is very little currently available to alleviate symptoms of COPD, prevent exacerbations, preserve optimal lung function, and improve daily living activities and quality of life. Many patients will use medication chronically for the rest of their lives, with the need for increased doses and additional drugs during exacerbations. Medications that are currently prescribed for COPD patients include: fast-acting β2-agonists, anticholinergic bronchodilators, long-acting bronchodilators, antibiotics, and expectorants. Amongst the currently available treatments for COPD, short term benefits, but not long term effects, were found on its progression, from administration of anti-cholinergic drugs, β2 adrenergic agonists, and oral steroids.
Short and long acting inhaled β2 adrenergic agonists achieve short-term bronchodilation and provide some symptomatic relief in COPD patients, but show no meaningful maintenance effect on the progression of the disease. Short acting β2 adrenergic agonists improve symptoms in subjects with COPD, such as increasing exercise capacity and produce some degree of bronchodilation, and even an increase in lung function in some severe cases. The maximum effectiveness of the newer long acting inhaled, β2 adrenergic agonists was found to be comparable to that of short acting β2 adrenergic agonists. Salmeterol was found to improve symptoms and quality of life, although only producing modest or no change in lung function. In asthmatics, however, β2 adrenergic agonists have been linked to an increased risk of death, worsened control of asthma, and deterioration in lung function. β2-agonists, such as albuterol, help to open narrowed airways. The use of β2-agonists can produce paradoxical bronchospasm, which may be life threatening to the COPD patient. In addition, the use of β2-agonists can produce cardiovascular effects, such as altered pulse rate, blood pressure and electrocardiogram results. In rare cases, the use of β2-agonists can produce hypersensitivity reactions, such as urticaria, angioedema, rash and oropharyngeal edema. In these cases, the use of the β2-agonist should be discontinued. Continuous treatment of asthmatic and COPD patients with the bronchodilators ipratropium bromide or fenoterol resulted in a faster decline in lung function, when compared with treatment provided on a need basis, therefore indicating that they are not suitable for maintenance treatment. The most common immediate adverse effect of β2 adrenergic agonists, on the other hand, is tremors, which at high doses may cause a fall in plasma potassium, dysrhythmias, and reduced arterial oxygen tension. The combination of a β2 adrenergic agonist with an anti-cholinergic drug provides little additional bronchodilation compared with either drug alone. The addition of ipratropium to a standard dose of inhaled β2 adrenergic agonists for about 90 days, however, produces some improvement in stable COPD patients over either drug alone. Anti-cholinergic agents were found to produce greater bronchodilation in combination with anti-cholinergic agents than β2 adrenergic agonists, in people with COPD. Overall, the occurrence of adverse effects with β2 adrenergic agonists, such as tremor and dysrhythmias, is more frequent than with anti-cholinergics. Thus, neither anti-cholinergic drugs nor β2 adrenergic agonists have an effect on all people with COPD; nor do the two agents combined.
Anti-cholinergic drugs achieve short-term bronchodilation and produce some symptom relief in people with COPD, but no improved long-term prognosis even with inhaled products. Most COPD patients have at least some measure of airways obstruction that is somewhat alleviated by ipratropium bromide. “The lung health study” found in men and women smokers spirometric signs of early COPD. Three treatments compared over a five year period found that ipratropium bromide had no significant effect on the decline in the functional effective volume of the patient's lungs whereas smoking cessation produced a slowing of the decline in the functional effective volume of the lungs. Ipratropium bromide, however, produced serious adverse effects, such as cardiac symptoms, hypertension, skin rashes, and urinary retention. Anticholinergic bronchodilators, such as ipratropium bromide, and theophylline derivatives, help to open narrowed airways. Long-acting bronchodilators help to relieve constriction of the airways and help prevent bronchospasm associated with COPD. Theophyllines have a small bronchodilatory effect in COPD patients whereas they have some common adverse effects, and they have a small therapeutic range given that blood concentrations of 15-20 mg/l are required for optimal effects. Adverse effects include nausea, diarrhea, headache, irritability, seizures, and cardiac arrhythmias, and they occur at highly variable blood concentrations and, in many people, they occur within the therapeutic range. The theophyllines' doses must be adjusted individually according to smoking habits, infection, and other treatments, which is cumbersome. Although theophyllines have been claimed to have an anti-inflammatory effect in asthma, especially at lower doses, none has been reported in COPD, although their bronchodilating short-term effect appears to be statistically different from placebo. The adverse effects of theophyllines and the need for frequent monitoring limit their usefulness. There is no evidence that anti-cholinergic agents affect the decline in lung function, and mucolytics have been shown to reduce the frequency of exacerbations but with a possible deleterious effect on lung function. The long-term effects of β2 adrenergic agonists, oral corticosteroids, and antibiotics have not yet been evaluated, and up to the present time no other drug has been shown to affect the progression of the disease or survival.
Oral corticosteroids elicit some improvement in baseline functional effective volume in stable COPD patients whereas systemic corticosteroids have been found to be harmful at least producing some osteoporosis and inducing overt diabetes. The longer term administration of oral corticosteroids may be useful in COPD, but their usefulness must be weighed against their substantial adverse effects. Inhaled corticosteroids have been found to have no real short-term effect on airway hyper-responsiveness to histamine, but a small long-term effect on lung function, e.g., in pre-bronchodilator functional effective volume. Fluticasone treatment of COPD patients showed a significant reduction in moderate and severe (but not mild) exacerbations, and a small but significant improvement in lung function and six minute walking distance. Oral prednisolone, inhaled beclomethasone or both had no effects in COPD patients, but lung function improved oral corticosteroids. Mucolytics have a modest beneficial effect on the frequency and duration of exacerbations but an adverse effect on lung function. Neither N-acetylcysteine nor other mucolytics, however, have a significant effect in people with severe COPD (functional effective volume<50%) in spite of evidencing greater reductions in frequency of exacerbation. N-acetylcysteine produced gastrointestinal side effect. Long-term oxygen therapy administered to hypoxaemic COPD and congestive cardiac failure, patients, had little effect on their rates of death for the first 500 days or so, but survival rates in men increased afterwards and remained constant over the next five years. In women, however, oxygen decreased the rates of death throughout the study. Continuous oxygen treatment of hypoxemic COPD patients (functional effective volume<70% predicted) for 19.3 years decreased overall risk of death. To date, however, only life style changes, smoking cessation and long term treatment with oxygen (in hypoxaemics), have been found to alter the long-term course of COPD.
Antibiotics are also often given at the first sign of a respiratory infection to prevent further damage and infection in diseased lungs. Expectorants help loosen and expel mucus secretions from the airways, and may help make breathing easier.
In addition, other medications may be prescribed to manage conditions associated with COPD. These may include: diuretics (which are given as therapy to avoid excess water retention associated right-heart failure), digitalis (which strengthens the force of the heartbeat), painkillers cough suppressants, and sleeping pills. This latter list of medications help alleviate symptoms associated with COPD but do not treat COPD.
Thus, there is very little currently available to alleviate symptoms of COPD, prevent exacerbations, preserve optimal lung function, and improve daily living activities and quality of life.
Severe acute respiratory syndrome (SARS) is a respiratory illness that has recently been reported in Asia, North America, and Europe. In general, SARS patients initial experience a fever of greater than 100.4° F. (>38.0° C.). This may be accompanied or followed by headache, an overall feeling of discomfort, and body aches. Certain patients also experience respiratory symptoms. Following 2 to 7 days, SARS patients may also develop a dry cough and experience breathing trouble. SARS appears to spread primarily by close person-to-person contact. The majority of SARS patients appear to have been involved people who cared for or lived with others with SARS, or had direct contact with an infectious material (e.g., respiratory secretions) from another patient with SARS. Potential ways in which SARS can be spread include touching the skin of other people or objects that are contaminated with infectious droplets and then touching your eye(s), nose, or mouth. This can happen when someone who is sick with SARS coughs or sneezes droplets onto themselves, other people, or nearby surfaces.
Scientists at the Centers for Disease Control and Prevention (CDC) and other laboratories have detected a previously unrecognized coronavirus in patients with SARS: SARS-CoV, which is the leading hypothesis for the cause of SARS The sequence of SARS-CoV has been sequenced and all of the sequence, except for the leader sequence, was derived directly from viral RNA. The genome of the SARS coronavirus is 29,727 nucleotides in length and the genome organization is similar to that of other coronaviruses. Open reading frames have been identified that correspond to the predicted polymerase protein (polymerase 1a, 1b), spike protein (S), small membrane protein (E), membrane protein (M) and nucleocapsid protein (N)
Researchers worldwide are been working frantically to develop a treatment for SARS. Currently no treatment has been found to be effective at stopping the SARS-CoV coronavirus associated with SARS. The antiviral drugs currently used, or considered, for treating SARS include ribavirin, 6-azauridine, pyrazofurin, mycophenolic acid, and glycyrrhizin. However, all these drugs have serious side effects (e.g., side effects of glycyrrhizin include raised blood pressure and lowered potassium levels). Treatment with the anti-inflammatory drug methylprednisolone has been shown achieve some improvement in SARS patients (So, L. K., et al., “Development of a standard treatment protocol for severe acute respiratory syndrome”, Lancet 361(9369): 1615-7, 2003).
Dehydroepiandrosterones are non-glucocorticoid steroids. DHEA, also known as 5androsten-3 beta-ol-17-one and DHEA sulfate (DHEA-S), a sulfated form of DHEA, are endogenous hormones secreted by the adrenal cortex in primates and a few non-primate species in response to the release of ACTH. DHEA is a precursor of both androgen and estrogen steroid hormones important in several endocrine processes. Current medical use of DHEA is limited to controlled clinical trials, and as a food supplement, and is thought to have a role in levels of DHEA in the central nerve system (CNS), and in psychiatric, endocrine, gynecologic, obstetric, immune, and cardiovascular functions.
DHEA-S or its pharmaceutically acceptable salts are believed to improve uterine cervix maturation and uterine musculature sensitivity to oxytocin in late phase pregnancy. DHEA-S and its pharmaceutically acceptable salts are thought to be effective in the therapy for dementia, for the therapy of hyperlipemia, osteoporosis, ulcers, and for disorders associated with high levels of, or high sensitivity to adenosine, such as steroid-dependent asthma, and other respiratory and lung diseases. Dehydroepiandrosterone itself was administered intravenously previously, subcutaneously, percutaneously, vaginally, topically and orally in clinical trials. In preformulation studies, however, the anhydrous form of DHEA sodium sulfate (DHEA-SNa) was found to be unstable to humidity, and its dihydrate form (DHEA-SNa) was found to be more stable under conditions of normal humidity.
As is known, various operations may be performed on medicinal agents during pharmaceutical processing that often affect the physicochemical properties and stability of the compounds. Prolonged grinding of the dehydroepiandrosterone sodium sulfate dihydrate produced a decrease in crystallinity and loss of hydration water; the latter decreasing storage stability and producing DHEA, its degradation product.
Accordingly, there is a need for a powder formulation of dehydroepiandrosterone compounds, their analogues and salts, that will show good dispersibility and shelf stability, as well as appropriate respirable properties. Such formulation would make it possible to deliver the dehydroepiandrosterone compounds, analogues and salts in a highly efficacious and cost effective manner.
U.S. Pat. No. 5,527,789 discloses a method of combating cancer in a subject by administering to the subject dehydroepiandrosterone (DHEA) or DHEA-related compound, and ubiquinone to combat heart failure induced by the DHEA or DHEA-related compound.
U.S. Pat. No. 6,087,351 discloses an in vivo method of reducing or depleting adenosine in a subject's tissue by administering to the subject dehydroepiandrosterone (DHEA) or DHEA-related compound. U.S. Pat. No. 6,087,351 discloses that solid particulate compositions containing respirable dry particles of micronized active compound may be prepared by grinding dry active compound with a mortar and pestle, and then passing the micronized composition through a 400 mesh screen to break up or separate out large agglomerates. Also, a solid particulate composition comprised of the active compound may optionally contain a dispersant which serves to facilitate the formation of an aerosol; and a suitable dispersant is lactose, which may be blended with the active compound in any suitable ratio (e.g., a 1 to 1 ratio by weight).
DHEA and DHEA-S have been described to treat COPD (U.S. patent application Ser. No. 10/454,061, filed Jun. 3, 2003, and International Application No. PCT/US02/12555, filed Apr. 21, 2002, published Oct. 31, 2002).